Fig. 4

Metabolic milieu of tumor microenvironment and its impact on the functioning of immunotherapies or T cells. (A) Metabolic struggle and/or metabolic reprogramming transpire between various tumor-infiltrating immune cells and tumor cells. Both T cells and tumor cells preferentially utilize glucose to meet their energy demands. Due to high proliferation potential and high energy needs, tumor cells metabolize most of the glucose through aerobic glycolysis and produce high levels of lactic acid (lactate) in the TME, thereby, decreasing glucose availability for immune cells. The lactate-enriched and glucose-deprived TME impairs T cell functioning, recruits more (regulatory T cells) Tregs, and polarizes microglial cells towards a pro-tumorigenic phenotype and tumor-associated macrophages (TAMs). There is further competition for amino acids, including glutamine/glutamate and tryptophan between T cells, myeloid-derived suppressor cells (MDSCs), and tumor cells. The availability of these amino acids in the TME that modulate T cell-mediated immune response, such as kynurenine (a product of tryptophan catabolism) produced by indoleamine 2,3-dioxygenase 1 (IDO1) present in tumor cells, MDSCs, and TAMs blocks activation of T cells and promotes the recruitment and production of immunosuppressive Treg cells. The brain microenvironment has high glutamine and tryptophan; therefore, tumor cells easily adapt to the brain microenvironment utilizes these amino acids for their growth and development. Lactate production in the TME also increases the expression of PD-1 on T cells and PD-L1 on tumor cells and suppresses the activity of immune cells. (B) The immunotherapeutic response of ITs could be enhanced by targeting the various metabolic regulators of tumor cells and immune cells. The utilization of inhibitors that specifically target glucose transporters (GLUT1), lactate production, IDO1 activity, and glutamine utilization in tumor cells could be a potential therapeutic strategy to enhance the efficacies of ITs in brain metastasis.